Goldschmidt was called up to the majors on August 1, 2011, becoming the first Texas State position player to play in the major leagues.[7] At the time of his call-up, he was leading the minors with 30 home runs. Goldschmidt tallied a base hit in his first at-bat on August 1, and hit his first home run the next day off San Francisco Giants pitcher Tim Lincecum. In his rookie season, Goldschmidt batted .250 with 8 home runs and 26 RBI in 48 games.

In Game 3 of the NLDS playoffs against the Brewers, Goldschmidt hit a grand slam home run to extend the team's lead in its first victory of the series. His homer was the third grand slam by a rookie in MLB postseason history.[8] The Diamondbacks lost the series in five games, and Goldschmidt batted .438 with 6 RBI and an OBP of .526.

During the 2013 MLB season, Goldschmidt was selected to the National League all-star team. Goldschmidt collected one of only three hits for the National League team, and the only extra-base hit, when he doubled with two outs in the ninth inning. On August 13, he hit a game-tying home run against the Baltimore Orioles in the bottom of the ninth inning to send the game into extra innings. Goldschmidt then hit a walk-off home run in the bottom of the eleventh, becoming the first Diamondbacks player to record game-tying and walk-off home runs in the same game. In 160 games that season, he attained a .302 batting average, 36 home runs, and 125 RBI. Goldschmidt finished second in the NL MVP voting, behind Pittsburgh Pirates outfielder Andrew McCutchen. He led MLB with four walk-off hits in 2013.[9]

In 2014, Goldschmidt batted .300 with 19 home runs, 75 runs, and 69 RBIs. His season came to an end on August 1st when Pittsburgh Pirates pitcher Ernesto Frieri hit him in his hand with a pitch. His hand was broken as a result, and he spent the rest of the year on the disabled list. Goldschmidt was the starting first baseman for the NL in the 2014 MLB All-Star Game.

On June 10, 2015, Goldschmidt hit his 100th career home run against Brett Anderson of the Los Angeles Dodgers. At the time of his 100th home run, Goldschmidt was sixth on the Diamondbacks' all-time home run list.[10] Later that year, Goldschmidt was again the starting first baseman for the NL in the All-Star Game. Goldschmidt attained a .321 batting average with 33 home runs and 110 RBI in 2015. He won his second Gold Glove Award and Silver Slugger Award.[11] For the second time in three seasons, Goldschmidt was voted the runner-up for the NL MVP award, this time finishing behind Washington Nationals outfielder Bryce Harper.

In 2016, Goldschmidt batted .297 with 24 home runs, 106 runs, and 95 RBIs in 579 at-bats. Goldschmidt was again named to the NL All-Star Team, to play in San Diego where he went 0 for 3, recording a fielder's choice in the ninth inning.

On August 3, 2017, Goldschmidt hit three home runs in a game for the first time, bolstering the Diamondbacks' 10–8 win over the Chicago Cubs.[12] For the 5th time in his career, Goldschmidt would be named to the NL All-Star Team. On September 13, 2017, in a game against the Colorado Rockies, Goldschmidt would record his 1000th career hit. Goldschmidt would finish the 2017 season batting .297 with 36 home runs, 117 runs, and 120 RBI. After the season, Goldschmidt would be awarded his third Gold Glove Award and Silver Slugger Award. He also finished 3rd in NL MVP Voting.

In the 2017 National League Wild Card Game, Goldschmidt would hit a 3-run home run in the 1st inning that would help the Diamondbacks to win 11-8 over the Rockies. During the NLDS, Goldschmidt would underperform, batting only .091. The Diamondbacks would go on to lose the series to the Los Angeles Dodgers.

Through the first 20 games in May of the 2018 season, Goldschmidt would struggle, managing to get only 7 hits out of 73 at-bats. At the time, this would sink his batting average for the season to just .198. Goldschmidt would dramatically improve into the following month however, as he would have a .390 batting average between the dates of June 1 and July 3. For the month of June, he would be named the National League Player of the Month for the first time in his career. His efforts would be enough for him to earn a spot on the NL All-Star Team for a 6th consecutive year. On August 3, 2018, Goldschmidt would hit his 200th career home run against Chris Stratton of the San Francisco Giants. Goldschmidt is now second on the Diamondback's all-time home run list. Goldschmidt would finish the 2018 season batting .290 with 33 home runs, 95 runs, and 83 RBI.

Goldschmidt met his future wife, Amy, during his freshman year at Texas State; the couple married in October 2010.[13] The couple's first child, a son, was born in September 2015.[14][15] Goldschmidt became an evangelical Christian as an adult; he has Jewish as well as European ancestry.[16][17]